EP2111222B1

EP2111222B1 - Delivery devices containing encapsulated active pharmaceutical ingredients

Info

Publication number: EP2111222B1
Application number: EP08729580.4A
Authority: EP
Inventors: Andrew Loxley; David Fairhurst; Garry Thomas Gwozdz; Mark Mitchnick; Abhijit Gokhale
Original assignee: Particle Sciences Inc
Current assignee: Lubrizol Life Science Health Inc
Priority date: 2007-02-12
Filing date: 2008-02-12
Publication date: 2018-06-20
Anticipated expiration: 2028-02-12
Also published as: EP3391874A3; US20100034863A1; US10258571B2; US20190254974A1; EP2111222A1; EP2111222A4; EP3391874A2; WO2008100876A1

Description

FIELD OF THE INVENTION

The present invention relates to vaginal ring delivery devices comprising a nondegradable biocompatible ring matrix with polymer encapsulated active pharmaceutical ingredients dispersed as particles within the matrix of the ring; and one or more active pharmaceutical ingredients separately dispersed in the ring matrix, wherein said polymer encapsulation material encapsulates the one or more active pharmaceutical ingredients via a method selected from a melt-chill process, a solvent emulsification process, or spray-drying.
The invention is set out in the claims attached hereto.

BACKGROUND OF THE INVENTION

Effective delivery of an active pharmaceutical ingredient is challenging. Hydrophobic active ingredients present challenges associated with poor aqueous solubility and slow dissolution rate while hydrophilic active ingredients, though readily soluble in aqueous environments, are poorly absorbed due to membrane impermeability and/or enzymatic degradation. While separately they present a formidable challenge, delivering both in a single device is exponentially more difficult. A multitude of drug delivery devices attempting to address these challenges and provide for release of pharmaceutically active ingredients in a controlled and continuous rate for a prolonged period of time have been described.
For example, vaginal ring technologies have been described providing for a once-a-month, or once-every-three to twelve month dosing regimen. Existing vaginal ring systems are typically manufactured from silicone elastomers and/or ethylene vinyl acetate polymers. See, for example, U.S. Patent 4,016,251 . Release from vaginal rings is generally controlled by diffusion of the active pharmaceutical ingredient and/or erosion of the ring matrix. Manufacture of existing vaginal ring systems is fairly complex as existing rings comprise an inner reservoir or core containing the active pharmaceutical ingredient and an outer silicone elastomer or ethylene vinyl acetate polymer shell. Further, in existing rings, diffusion from the core to the shell reduces the overall rate of diffusion so that extended metered release into the vaginal lumen is obtained. However, cores and shells that are amenable to passage of hydrophobic compounds are not typically amenable to passage of hydrophilic compounds. Hence, delivery of dissimilar molecules with existing ring technologies is challenging.
EP1466631 discloses a formulation for cartilage tissue formation, comprising a drug having a chondrogenesis-promoting action, a biodegradable and/or biocorrosive polymer, and a porous matrix and/or a hydrogel, wherein the porous matrix and the hydrogel substantially do not inhibit cartilage repair.
US2004033264 discloses compositions and methods to control the release of relatively low molecular weight therapeutic species through hydrogels by first dispersing or dissolving such therapeutic species within relatively hydrophobic rate modifying agents to form a mixture. The mixture is formed into microparticles that are dispersed within bioabsorbable hydrogels, so as to release the water soluble therapeutic agents in a controlled fashion.
US 2005/0276836 A1 discloses a vaginal device for delivering therapeutical and/or health-promoting agents. The vaginal device is partly or completely coated by, covered by or combined with a coating or covering comprising a film, foam, strip, cap, cup or particles. The coating of the device comprises a mucoadhesive composition comprising a therapeutical and/or health-promoting agent.
US 2006/240071 A1 discloses an intravaginal contraceptive device having a biocompatible support structure constructed and configured to be inserted into a mammal's vagina without substantially blocking the cervix, coated by a multilayer coating having one or more biodegradable polymers. The multilayer coating can be constructed and formed of materials such that the multilayer coating dissolves over a period of at least three days, wherein each layer of the multilayer coating includes a spermicidal and/or spermiostatic composition and is constructed and formed to dissolve at varying times. Additionally, the multilayer coating is preferably constructed and formed of materials effective to provide a sustained release of a spermicidally or spermiostatically effective amount of the composition for at least three days. Accordingly, there are a number of areas in which current vaginal ring technology can be improved. These include manufacturing ease, cost, multi-drug delivery, and environmental impact.

SUMMMARY OF THE INVENTION

An aspect of the present invention relates to the vaginal ring delivery device for active pharmaceutical ingredients of claim 1 comprising a nondegradable biocompatible ring matrix and polymer encapsulated active pharmaceutical ingredients dispersed as particles within the matrix of the ring. The matrix also contains one or more active pharmaceutical ingredients separately dispersed in the ring matrix. The matrix is shaped to facilitate delivery of the active pharmaceutical ingredient to its site of therapeutic action.
Another aspect of the present invention relates to the method of claim 7 for the production of these vaginal ring delivery devices and to these vaginal ring delivery devices for use in delivering one or more active pharmaceutical ingredients to a subject, the use comprising administering to the subject these vaginal ring delivery devices. Another aspect of the present invention relates to a vaginal ring with a ring body having an irregular surface to increase surface area of the vaginal ring.
Yet another aspect of the present invention relates to a surface coating which minimizes bio-interaction of a vaginal ring delivery device for an activated pharmaceutical ingredient which comprises one or more anionic or nonionic hydrophilic polymers and which is applied as a coating to the delivery device.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a schematic of an exemplary delivery device of the present invention. The matrix is shaped as a vaginal ring and comprises encapsulated active pharmaceutical ingredients dispersed throughout the matrix ring. The matrix itself contains a separate active pharmaceutical ingredient.
Figure 2 is a cross-sectional view of the matrix of Figure 1 and shows dispersion of the encapsulated active pharmaceutical ingredients throughout the matrix.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides vaginal ring delivery devices for active pharmaceutical ingredients, methods for the production of these vaginal ring delivery devices, and these vaginal ring delivery devices for use in delivering an active pharmaceutical ingredient or active pharmaceutical ingredients to a subject. The active pharmaceutical ingredient vaginal ring delivery devices of the present invention are easier to manufacture than existing vaginal ring delivery devices and provide for multi-agent delivery. Further, manufacturing costs for these vaginal ring delivery devices are expected to be decreased.
The vaginal ring delivery devices of the present invention comprise a nondegradable biocompatible matrix. Selection of the biocompatible matrix material and its shape, as well as its degradation characteristics, is based upon the active pharmaceutical ingredient or active pharmaceutical ingredients to be delivered, the desired length of action, and the targeted site for delivery in a subject.
Delivery of an active pharmaceutical ingredient or active pharmaceutical ingredients to the vaginal lumen can be achieved with a nondegradable matrix material shaped as a vaginal ring or as an intra-uterine device. Exemplary matrix materials for use in the vaginal ring delivery device of the present invention include, but are in no way limited to, ethylene-vinyl acetate (EVA), silicones, waxes, lipids and hydrophilic compounds.
Vaginal ring delivery devices of the present invention further comprise polymer encapsulated active pharmaceutical ingredients dispersed as particles within the matrix of the ring; and one or more active pharmaceutical ingredients separately dispersed in the ring matrix. Encapsulated active pharmaceutical ingredients may be dispersed evenly or unevenly in the ring matrix.
When encapsulated, it is preferred that the active pharmaceutical ingredient or active pharmaceutical ingredients be microencapsulated, and more preferably nanoencapsulated. Thus, encapsulated active pharmaceutical ingredients used in the vaginal ring delivery devices of the present invention are preferably 1000 microns or less, more preferably 100 microns or less, more preferably 1 micron or less, and most preferably 0.1 micron or less in size. A preferred size range for nanoencapsulated active pharmaceutical ingredients used in the vaginal ring delivery devices of the present invention is 25 to 1000 nm.
Examples of encapsulation materials for the active pharmaceutical ingredient or active pharmaceutical ingredients are polymers and include, but are not limited to, natural or synthetic waxes or wax-like materials such as beeswax, carnauba wax, hydrogenated vegetable oils, stearyl alcohol, and cetyl alcohol, polymeric materials such as polyethylene, polyethylene glycol, polyvinyl alcohol, and silicone polymers, naturally occurring gelling agents such as gelatin, gellan gum, carrageenans, and alginates, and combinations thereof.
Various methods are used to encapsulate the active pharmaceutical ingredient or active pharmaceutical ingredients for use in the vaginal ring delivery devices of the present invention, the encapsulation method being selected from a melt-chill process, a solvent emulsification process, or spray-drying. For example, a melt-chill process can be used. This process comprises dissolving or dispersing the active pharmaceutical ingredient or active pharmaceutical ingredients into the encapsulation material at a temperature above the melt point of the encapsulation material, emulsifying the mixture into a non-miscible carrier using suitable emulsifying agents, cooling the emulsified mixture to form a solid, and forming particles from the solid. Alternatively, a solvent emulsification process can be used. This process comprises dissolving the active pharmaceutical ingredient or active pharmaceutical ingredients and the encapsulation material into an appropriate solvent, emulsifying the resultant mixture into a non-miscible carrier using suitable emulsifying agents, and removing the solvent to form the particles. In both the melt-chill process and the solvent emulsification process, the non-miscible carrier can be removed prior to or during processing of the encapsulated active pharmaceutical ingredient or active pharmaceutical ingredients into the delivery form, or may be a material that becomes part of the delivery form. Additional exemplary encapsulation methods suitable to forming encapsulated active pharmaceutical ingredients for use in the vaginal ring delivery devices of the present invention include, but are not limited to, spray-drying, which comprises dissolving or dispersing the active pharmaceutical ingredient or active pharmaceutical ingredients into the encapsulation material in a liquid state either through raising the temperature above the melt point or use of a solvent for the encapsulation material, atomizing the resultant mixture, and forming particles of encapsulated active pharmaceutical ingredient or active pharmaceutical ingredients through cooling or removal of the solvent.
Active pharmaceutical ingredients which can be encapsulated and dispersed as particles into the matrix materials of the vaginal ring delivery devices of the present invention include, but are in no way limited to, drugs, including vaccines, nutritional agents, cosmeceuticals and diagnostic agents. Examples of active pharmaceutical ingredients for use in the present invention include, but are not limited to, analgesics, anti-anginal agents, anti-arrhythmic agents, anti-angiogenic agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, anti-depressants, anti-diabetic agents, anti-epileptic agents, anti-fungal agents, anti-gout agents, antihypertensive agents, anti-inflammatory agents, anti-malarial agents, anti-migraine agents, anti-muscarinic agents, antineoplastic agents, anti-obesity agents, anti-osteoporosis agents, anti-parkinsonian agents, anti-protozoal agents, anti-thyroid agents, anti-urinary incontinence agents, anti-viral agents, anxiolytics, beta-blockers, cardiac inotropic agents, cognition enhancers, corticosteroids, COX-2 inhibitors, diuretics, erectile dysfunction improvement agents, essential fatty acids, gastrointestinal agents, histamine receptor antagonists, hormones, immunosuppressants, keratolyptics, leukotriene antagonists, lipid regulating agents, macrolides, muscle relaxants, non-essential fatty acids, nutritional agents, nutritional oils, protease inhibitors and stimulants.
In the vaginal ring delivery devices of the present invention, one or more non-encapsulated active pharmaceutical ingredient is also added to the matrix material. In fact, multiple active pharmaceutical ingredients can be encapsulated and dispersed as particles and/or incorporated directly in the ring matrix. In general, an active pharmaceutical ingredient added directly to the device matrix is compatible with the matrix. Thus, if the matrix is comprised of silicone or ethylene-vinyl acetate then any active pharmaceutical ingredient added directly to the matrix is generally hydrophobic. If the matrix is comprised of a hydrophilic polymer then any active pharmaceutical ingredient added directly to matrix is generally hydrophilic.
However, it has been found that differences in the hydrophilic or hydrophobic nature of the encapsulated active pharmaceutical ingredients dispersed in the matrix alter the release of an active pharmaceutical ingredient dispersed directly in the matrix as compared to a matrix containing only the directly dispersed active pharmaceutical ingredient. For a vaginal ring, it was found that encapsulating particles alone can impact release. Specifically, a ring matrix comprising encapsulated polymer particles dispersed within the matrix of the ring and an active pharmaceutical ingredient separately dispersed in that matrix released the active pharmaceutical ingredient at a rate closer to zero order as compared to a matrix which did not comprise encapsulated polymer particles. Accordingly, changes in release profile must be considered when designing vaginal ring delivery devices of the present invention.
The present invention further relates to a surface coating for vaginal ring delivery devices comprising an anionic or nonionic hydrophilic polymer or polymers to minimize bio-interaction. For example, a coating of polyethylene glycol may be applied to a vaginal ring delivery device to inhibit adhesion of endogenous proteins and microbial growth to the device. Additional examples of polymers useful as surface coatings include, but are not limited to, poly (vinyl pyrrolidone), polyvinyl alcohol, PEO, and PEO-PPO copolymers, poly(acrylic acid), poly(methacrylic acid), and poly(styrene sulfonate). Also see springerlink with the extension .com/content/ t234483257116u1q/ of the world wide web. In a preferred embodiment, this surface coating is applied to a vaginal ring delivery device as described herein. Application of a coating to the vaginal ring delivery device of the present invention provides the advantage of improved safety. Further, the coating can be selected to provide for more reliable long term activated pharmaceutical ingredient release. For example, a hydrophobic matrix containing a hydrophilic active pharmaceutical ingredient can be coated with a hydrophilic coating to provide a molecular layer of water around the vaginal ring to aid in diffusion of the active pharmaceutical ingredient. In this embodiment, the coating provides a micro-environment to facilitate the transfer of the active pharmaceutical ingredient.
As shown in Figures 1 and 2, the invention relates to vaginal ring delivery devices. Release from the vaginal ring device of the present invention is diffusion controlled. In a preferred embodiment, vaginal rings produced in accordance with the present invention will deliver the active pharmaceutical ingredient or active pharmaceutical ingredients at a rate comparable to existing technologies. Further, vaginal rings produced in accordance with the present invention are expected to be useful for delivery of at least two or more active pharmaceutical ingredients dispersed in the matrix material at acceptable rates for at least 10 days, preferably 90 days. As shown in Figures 1 and 2, a vaginal ring 1 with two or more active pharmaceutical ingredients may comprise a first encapsulated active pharmaceutical ingredient 2 dispersed in the matrix 3 and a second non-encapsulated active pharmaceutical ingredient 4 added to the matrix material. Alternatively, it is disclosed that the delivery device may comprise more than one encapsulated active pharmaceutical ingredient dispersed in the matrix material. The matrix materials used in this vaginal ring delivery device of the present invention are flexible for ease in insertion and comfort during intercourse. Manufacture of vaginal rings in accordance with the present invention is cost-efficient.
In this embodiment of the vaginal ring delivery device of the present invention depicted in Figures 1 and 2, dispersion of an encapsulated hydrophobic active pharmaceutical ingredient or active pharmaceutical ingredients in a hydrophobic nondegradable matrix material results in a delivery device wherein the active pharmaceutical ingredient or active pharmaceutical ingredients must first pass through the encapsulation material much the same way an active pharmaceutical ingredient passes through the core in a two- part standard ring. An advantage of the vaginal ring delivery device of the present invention is that there is no need to make two-part rings.
The vaginal ring depicted in Figure 1 and 2 is a smooth ring. However, vaginal rings of the present invention may also have an irregular surface with, for example, dimples or divets in the surface of the ring to increase surface area. In one embodiment, these dimples or divets serve as surface pockets that are filled with a second active pharmaceutical ingredient-containing matrix. In this embodiment, the ring itself releases one active pharmaceutical ingredient while the dimples or divets release another active pharmaceutical ingredient. The matrix in the dimples or divets may or may not be degradable.
The vaginal ring delivery devices of the present invention are useful in administering one or more active pharmaceutical ingredients to a subject. Preferred subjects are mammals. More preferred subjects are humans. The delivery device of the present invention with a vaginal ring-shaped matrix is administered by insertion of the delivery device into the vaginal lumen.
The following nonlimiting example is provided to further illustrate the present invention.

EXAMPLE

Example 1: Vaginal Ring Production

Vaginal rings were manufactured using injection molding. The ring matrix is either melted, as in the case of EVA, or catalytically formed from an elastomer, as with silicones. EVA vaginal rings were molded in a two-part aluminum mold. The rings were slightly smaller in diameter than the vaginal rings of Akzo Nobel. A target loading of 50 mg of active pharmaceutical ingredient is likely, which is about 1% by weight of active pharmaceutical ingredient. However, content of active pharmaceutical ingredient is ultimately determined by application and may vary substantially. Silicone rings are made in a similar mold.

Example 2: Melt-Chill Production of Bioadhesive Particles for a Film Delivery Device

Yellow carnauba, used as the particle encapsulation material, is melted along with the active pharmaceutical ingredient to form a single phase, and emulsified into a solution mixture of 1% Brij700 non-ionic emulsifier and 1% chitosan in 1% acetic acid (to dissolve the chitosan). After emulsification the dispersion is cooled to form cationic particles containing the encapsulated active pharmaceutical ingredient.

Claims

A vaginal ring delivery device for an active pharmaceutical ingredient comprising
a nondegradable biocompatible ring matrix;

polymer encapsulated active pharmaceutical ingredients dispersed as particles within the matrix of the ring; and

one or more active pharmaceutical ingredients separately dispersed in the ring matrix,
wherein said polymer encapsulation material encapsulates the one or more active pharmaceutical ingredients via a method selected from a melt-chill process, a solvent emulsification process, or spray-drying.
The vaginal ring delivery device of claim 1 wherein the vaginal ring is smooth.
The vaginal ring delivery device of claim 1 wherein the vaginal ring has an irregular surface to increase the surface area of the vaginal ring.
The vaginal ring delivery device of claim 3 wherein the irregular surface of the vaginal ring is dimpled or divetted.
The vaginal ring delivery device of claim 4 wherein the dimples are filled with a second active pharmaceutical ingredient-containing matrix.
The vaginal ring delivery device of any of claims 1 to 5 further comprising a surface coating of one or more anionic or nonionic hydrophilic polymers applied to the delivery device to minimize bio-interaction.
A method to prepare the vaginal ring delivery device of any of claims 1 to 6, the method comprising encapsulating the one or more active pharmaceutical ingredients with the polymer encapsulation material using a method selected from a melt-chill process, a solvent emulsification process, or spray-drying.
The vaginal ring delivery device of any of claims 1 to 6 or the vaginal ring delivery device prepared by the method of claim 7, for use in delivery of the one or more active pharmaceutical ingredients to a subject, the use comprising administering to the subject the vaginal ring delivery device of any of claims 1 to 6 or the vaginal ring delivery device prepared by the method of claim 7.